Summary: 3.1 Intestinal Homeostasis | Jerry Wells

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• 1 Intestinal homeostasis

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• Which 4 eptihelial cells reside in the intestine and what are their functions?

  1: absorptive cells/enterocytes
  2: goblet cells: mucin production
  3: endocrine cells: satiety, peristalsis
  4: Paneth cells: a-ubial factors (only SI)

• How does NOD and TLR signalling in the epithelium occur?

  All TLRs (except TLR3) -> MyD88 -> NF-kB + MAPK
  TLR3/4 -> TRIF -> type 1 IFN
  NOD1/2 -> RIP2 -> NF-kB + MAPK
  IkBs(a) inhibit NF-kB, but is Pi'd by IKK(IkB kinase), degrading it.

• What is the structure of mucus, and how is it distributed across the gut and why? How is it organized?

  Mucus has a net-like structure. Thickest in the colon, then in ileum, rest is similar.
  SI has thinner mucus due to a lower bact. load, but there are a-ubial peptides (facilitate absorption?)
  - intestinal lumen: extensive anaerobic ubiota
  - outer mucus layer (700 um): degenerated mucus, diluted a-ubials, some bacteria
  - inner mucus layer (100 um): firmly adherent, rich in a-ubials, sterile
  - colonic crypts (200 um): thick mucus, sterile, a-ubials production, cell barrier, underlying + intervening leukocytes

• How is the production of a-ubials regulated? (3)

  1: constitutive expression by enterocytes: a-defensins
  2: TLR/MyD88-dependent expression: Reg-3g
  3: NOD2-dependent expression in Paneth cells: subset of a-defensins 

• Which a-ubials and chemokines are important for IECs?

  IL-8 (IECs): chemoattractant for neutrophils
  Reg-3g/B (HIP/PAP, Paneth cells): inhibit bact growth in crypts
  a-defensin - human defensin 5 (Paneth cells): protection from infection
  B-defensins (IECs, leukocytes): autocrine pathways to epithelium and immune system

• Which 4 pathways are activated when bacteria breach the epithelial barrier?

  1: surface recognition (TLR), or endocytosis of PAMPs, or protein toxins -> NF-kB by pathogens
  2: adherence and secretion of toxins -> pro-infl genes by C. diff and B. fragilis
  3: injection of effectors by type III and IV secretory systems -> pro-infl genes by EPEC, EHEC, H. pylori
  4: invasion by Salmonella

   

• What is the vicious cycle of inflammation and permeability in the gut?

  inflammation -> increased epithelial permeability -> increased paracellular flow of inflammatory infiltrate from lumen -> etc.

• What are the 3 factors combined to cause IBD? What are the differences between UC and CD?

  genetic disposition, environmental agent(s), dysregulated immune response
  CD: SI and colon, deep inflammation. patchy areas
  UC: entire colon, mucosal inflammation, continuous area

   

• How are genetic and environmental factors involved in IBD?

  Genetic variations in immune/immunity regulation/epithelial permeability are associated with IBD.
  GF mice don't develop IBD. Monozygotic twins concordance is <100% (44-50% CD, 5-14% UC).

• How are microbiota affected in IBD?

  - dysbiosis: altered ubial composition, decreased colonization resistance
  - decrease of Firmicutes and Bacteroidetes, increaes of Proteobacteria and Actinobacteria
  - increase of pathobiontic adherent-invasive E. coli (AIEC),